Simultaneous determination of raltegravir and raltegravir glucuronide in human plasma by liquid chromatography-tandem mass spectrometric method

Raltegravir is a highly efficacious inhibitor of HIV integrase. Large pharmacokinetic variability has been reported in clinical trials and this could be due to glucuronidation of raltegravir, the only reported metabolism pathway. In order to precisely evaluate and monitor the raltegravir and raltegravir glucuronide simultaneously, a novel, sensitive and robust liquid chromatography-tandem mass spectrometric method was developed and validated for simultaneous determination of raltegravir and raltegravir glucuronide in human plasma. A simple protein precipitation with acetonitrile was utilized for plasma sample preparation prior to analysis. Baseline chromatographic separation was achieved on a ZORBAX Eclipse XDB-C8 using gradient elution mode. The run time was 9 min at a constant flow rate of 0.4 ml/min. The mass spectrometer was operated under a positive electrospray ionization condition. Excellent linearity (r(2) ≥ 0.9997) was achieved for raltegravir and raltegravir glucuronide in the range of 2-2000 nmol/l. The average recovery of raltegravir and raltegravir glucuronide was 105.8% and 102.2%, respectively. The precision (coefficient of variation) was 1.6-6.6% for raltegravir and 2.1-6.9 for raltegravir glucuronide, respectively. The accuracy was 98.6-106.1% for raltegravir and 96.3-100.3% for raltegravir glucuronide. The plasma samples were tested to be stable after nine freeze-thaw cycles and exposure to room temperature for 24 h. This well-validated assay was applied for the quantification of raltegravir and raltegravir glucuronide in plasma samples within 24 h after a single oral dose of 400 mg raltegravir in six healthy subjects.     

Synthesis of a D3-symmetric "trefoil" knotted cyclophane

A D(3)-symmetric knotted cyclophane, with a subgraph of trefoil topology, was synthesized by cyclization of a D(3)-symmetric scaffold. Control of configuration at the three metal-based stereocenters arises from a bascule/pivot mechanism.     

A water soluble vitamin B12-ReI fluorescent conjugate for cell uptake screens: use in the confirmation of cubilin in the lung cancer line A549

A water soluble vitamin B(12)-rhenium conjugate was synthesized and used in concert with intrinsic factor to screen for cubilin receptor-mediated uptake in lung cancer cells. Internalization of the conjugate demonstrated that it could be used to rapidly screen for the cubilin receptor in living cells, subsequently confirmed with Western blotting and RT-PCR.     

Nanocrystal self-assembly with rod-rod block copolymers

Two distinct morphologies of hexylselenophene-hexylthiophene rod-rod block copolymer films can be prepared depending on the molecular weight of the sample (see picture: left M(n) =12.9, right M(n) =3.9?kg?mol(-1) ). These polymers can be used to organize spherical CdSe nanocrystals (yellow) into either dispersed or aligned hierarchical structures. Scale bars: 200?nm.     

Challenges in chelating positron emitting copper isotopes: tailored synthesis of unsymmetric chelators to form ultra stable complexes

The synthesis of chelators that form high stability complexes with copper(II) isotopes and do not suffer from transchelation in vivo has been a goal for many chemists. Such chelators will facilitate the exploitation of the (64)Cu isotope (t(1/2) = 12.7 h, β(+) (19%); β(-) (39%); EC (41%)) for positron emission tomography imaging studies, which has a longer half life relative to the more commonly used (18)F (t(1/2) = 109.8 min) and (11)C (t(1/2) = 20.4 min) isotopes. One option is the CBTE2A chelator, which has been championed by Weisman, Wong and Anderson, and, more recently, alternate bifunctional chelator (BFC) versions have been synthesised. Improved synthetic methods are required for unsymmetric derivatisation of these chelators to allow more selective biomolecule attachment. This work investigates synthetic routes to form new unsymmetric chelating ligands via stepwise reaction of the bisaminal precursor, determines their X-ray structures and demonstrates cold copper(II) isotope complex formation.     

Sceliphrolactam, a polyene macrocyclic lactam from a wasp-associated Streptomyces sp

A previously unreported 26-membered polyene macrocyclic lactam, sceliphrolactam, was isolated from an actinomycete, Streptomyces sp., associated with the mud dauber, Sceliphron caementarium. Sceliphrolactam's structure was determined by 1D- and 2D-NMR, MS, UV, and IR spectral analysis. Sceliphrolactam displays antifungal activity against amphotericin B-resistant Candida albicans (MIC = 4 μg/mL, 8.3 μM).     

Optimization and evaluation of mixed-bed chemisorbents for extracting fission and activation products from marine and fresh waters

Chemically selective chemisorbents are needed to monitor natural and engineered waters for anthropogenic releases of stable and radioactive contaminants. Here, a number of individual and mixtures of chemisorbents were investigated for their ability to extract select fission and activation product elements from marine and coastal waters, including Co, Zr, Ru, Ag, Te, Sb, Ba, Cs, Ce, Eu, Pa, Np, and Th. Conventional manganese oxide and cyanoferrate sorbents, including commercially available Anfezh and potassium hexacyanocobalt(II) ferrate(II) (KCFC), were tested along with novel nano-structured surfaces (known as Self Assembled Monolayers on Mesoporous Supports or SAMMS) functionalized with a variety of moieties including thiol, diphosphonic acid (DiPhos-), methyl-3,4 hydroxypyridinone (HOPO-), and cyanoferrate. Extraction efficiencies were measured as a function of salinity, organic content, temperature, flow rate and sample size for both synthetic and natural fresh and saline waters under a range of environmentally relevant conditions. The effect of flow rate on extraction efficiency, from 1 to 70 mL min(-1), provided some insight on rate limitations of mechanisms affecting sorption processes. Optimized mixtures of sorbent-ligand chemistries afforded excellent retention of all target elements, except, Ba and Sb. Mixtures of tested chemisorbents, including MnO(2)/Anfezh and MnO(2)/KCFC/Thiol (1-3 mm)-SAMMS, extracted 8 of the 11 target elements studied to better than 80% efficiency, while a mixture of MnO(2)/Anfezh/Thiol (75-150 μm)-SAMMS mixture was able to extract 7 of the 11 target elements to better than 90%. Results generated here indicate that flow rate should be less of a consideration for experimental design if sampling from fresh water containing variable amounts of DOM, rather than collecting samples from salt water environments. Relative to the capability of any single type of chemisorbent tested, optimized mixtures of several sorbents are able to increase the number of elements that can be efficiently and simultaneously extracted from natural waters.